One approach to cancer therapy is to target the immune system (“immunotherapy”) rather than and/or in addition to targeting the tumor itself. One cancer immunotherapy approach targets cytotoxic T lymphocyte-associated antigen 4 (CTLA4; CD152), which is a cell surface receptor expressed on activated T cells. Binding of CTLA4 to its natural ligands, B7.1 (CD80) and B7.2 (CD86), delivers a negative regulatory signal to T cells, and blocking this negative signal results in enhanced T cell immune function and antitumor activity in animal models (Thompson and Allison Immunity 7:445-450 (1997); McCoy and LeGros Immunol. & Cell Biol. 77:1-10 (1999)). Several studies have demonstrated that CTLA4 blockade using antibodies markedly enhances T cell-mediated killing of tumors and can induce antitumor immunity (Leach et al., Science 271:1734-1736 (1996); Kwon et al. Proc. Natl. Acad. Sci. USA 94:8099-8103 (1997); Kwon et al., Natl. Acad. Sci. USA 96:15074-15079 (1999)).
The goal of treatment for metastatic cancer is to prolong survival. There are no approved or experimental agents that have been shown to improve survival in patients with melanoma or to induce tumor response in a large percentage of melanoma patients. In some cases, CTLA4 blocking agents have been shown to induce objective tumor responses in approximately 7-15% of patients with melanoma, but can cause serious side effects. No association of a predictive biomarker for survival benefit for an immunotherapy regimen has been established.